3-lower alkoxy-2h-1,2-benzothiazin-4-(3h)-one 1,1-dioxide



United States Patent US. Cl. 260-243 4 Claims ABSTRACT OF THE DISCLOSUREA 3-lower alkoxy-1,2-benzothiazin of the formula:

whereinRis lower alkyl.

These compounds are useful as an inhibitor of the enzyme urease.

This application is a divisional application of our copendingapplication, U.S. Ser. No. 666,949, filed Sept. 11, 1967.

The present invention relates to novel 3-alkoxy-2H-l,2-benzothiazin-4(3H)-one 1,1-dioxides of the formula:

wherein R is lower alkyl of 1 to 6 carbon atoms, preferably methyl.

The compounds of this invention are prepared by treating a compound ofthe formula:

wherein R is lower alkyl, for example, methyl, ethyl, propyl, and thelike, or aryl, for example pheny, by one of the two processes describedbelow.

In the first method, compound II is treated with silver carbonate in alower alkanol solvent at reflux temperature of the solvent.

The second method comprises treating compound II with tert-butylhypochlorite in a lower alkanol solvent at a temperature such as from toC.

The compounds of this invention are potent inhibitors of the enzymeurease and as such are useful in the oral treatment of ammonemic statesfound in severe liver disease or certain complications of uremicsyndrome such as uremic colitis.

The compounds act by inhibiting bacterial urease, for example, thatproduced by Proteus in the gastro-intestinal tract. They thereby preventammonia formation and concomitant systemic reabsorption of ammonia.

Because of their relative insolubility in the gastrointestinal fluid andtheir ability to act at low pH, the 1,2-

3,492,296 Patented Jan. 27, 1970 benzothiazine derivatives of thisinvention also inhibit urease present in the stomach.

The benzothiazine derivatives of this invention are to be administeredorally to a mammal having a body Weight of about 70 kg. at a dosage ofabout 250 to 700 mg. several times daily. The dosage may be adjusted inan amount sufficient to prevent or mitigate signs and symptoms of acutehepatic encephalopathy or to lower blood ammonia levels.

The benzothiazine derivatives may also be administered in cases of longterm chronic hepatic encephalopathy in divided closes with a total dailyintake of about 1 gm. in order to permit larger protein intakes amongthose individuals abnormally sensitive to increases of dietary proteinbecause of high blood ammonia. Likewise, it may be used as a medicinalsupplement in cases of uremic syndrome where ammonemiia is a problem.

In use, the compounds of this invention are combined with an inertpharmaceutical carrier, such as lactose, dicalcium phosphate, mannitoland compounded into dosage forms such as tablets, pills, capsules andthe like according to the pharmacists art. They may also be combinedwith other inert pharmaceutical diluents, such as water, syrup, andformulated to liquid dosage forms, such as suspensions and the like.

The starting compound II is prepared by treating a saccharin derivativeof the formula:

i l N-CI'LZCR;

s02 (II with an alkali metal alkoxide, such as sodium ethoxide in alower alkanol solvent such as ethanol at a temperature of from about 50to 55 C. The reaction is completed by neutralizing the excess base inthe reaction media by the addition of an acid. See also Zinnes et al.,J. Org. Chem., vol. 29, pp. 206870 (1964).

The following examples are included in order further to illustrate theinvention. Room temperatures referred to therein are from about 20 to 30C.

EXAMPLES 3 -methoxy-1,2-benzothiazin-3H-4-one 1,1-dioxide prepared bythe silver carbonate method A mixture of 24 g. (0.1 mole) of3-acetyl-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide, 25 g. (0.15 mole) ofsilver carbonate and 750 ml. of methanol is refluxed with stirring for 4hours. The mixture is filtered While hot and the filtrate allowed tostand at room temperature. The off-white crystals which separate arecollected to give 10.1 g. of produce, M.P. 210-217" C. dec. (sinters at205). Recrystallization from methanol gives material, M.P. 213-218 C.dec. (sinters at 205).

Analysis.--Calcd. for C H NO S; C, 48.01; H, 3.13; N, 6.22; S, 14.24.Found: C, 48.29; H, 3.28; N, 6.26; S, 14.19.

Prepared by the tert-butyl hypochlorite method A suspension of 12.0 g.(0.1 mole) of 3-acetyl-2H-1,2- benzothian-4(3H)-one 1,1 dioxide in ml.of methanol is protected from light and 50 ml. of 50% (w/v.) tertb utylhypochlorite in carbon tetrachloride is added slowly with sufficientcooling to maintain room temperature. The resulting solution is allowedto stand at room temperature for two hours and then refrigerated. Onstirring and scratching there is obtained 7.3 g. of product, M.P.213-218 C. dec. (sinters at 205).

3 4 What we claim is: claim 1 which comprises treating a compound ofthe 1. A compound of the formula: formula:

0 il 0 il 5 git-R,

OR it NH S62 S02 where R is lower alkyl or aryl with tert-butylhypochlorite in a lower alkanol solvent at a temperature of wherein R islower alkyl. 20 to 30 C.

2. The compound of claim 1 wherein R is methyl. 3. A process for theproduction of the compound of References Cited claim 1 which comprisesrefluxing a compound of the UNITED STATES PATENTS f l a 3,284,45011/1966 Kraaijeveld et a1. 260243 0 QTHER REFERENCES H Abe et al.; J.Pharm. Soc., Japan, vol. 76, pp. 1058-63 G o-R1 (1956 i NH HENRY R,JILES, Primary Examiner S 2 JOHN M. FORD, Assistant Examiner wherein Ris lower alkyl or aryl with silver carbonate US. Cl. X.R. in a loweralkanol solvent. 26G 999 4. A process for the production of a compoundof

